WO 95/14007 published May 26, 1995 discloses H3 receptor antagonists of the imidazole type.
WO99/24405 published May 20, 1999 discloses H3 receptor ligands of the imidazole type.
U.S. Pat. No. 5,869,479 issued Feb. 9, 1999 discloses compositions for the treatment of the symptoms of allergic rhinitis using a combination of at least one histamine H1 receptor antagonist and at least one histamine H3 receptor antagonist.
In view of the art""s interest in compounds which affect H3 receptors, novel compounds that are antagonists of H3 receptors would be a welcome contribution to the art. This invention provides just such a contribution.
The present invention provides novel compounds of structure I. 
or a pharmaceutically acceptable salt or solvate thereof, wherein:
(1) R1 is is selected from:
(a) aryl;
(b) heteroaryl;
(c) heterocycloalkyl
(d) alkyl;
(e) cycloalkyl; or
(f) alkylaryl;
wherein said R1 groups are optionally substituted with 1 to 4 substituents independently selected from:
(1) halogen (e.g., Br, F, or Cl, preferably F or Cl);
(2) hydroxyl (i.e., xe2x80x94OH);
(3) lower alkoxy (e.g., C1 to C6 alkoxy, preferably C1 to C4 alkoxy, most preferably C1 to C2 alkoxy, more preferably methoxy);
(4) xe2x80x94CF3;
(5) CF3Oxe2x80x94;
(6) xe2x80x94NR4R5;
(7) phenyl;
(8) xe2x80x94NO2,
(9) xe2x80x94CO2R4;
(10) xe2x80x94CON(R4)2 wherein each R4 is the same or different;
(11) xe2x80x94S(O)mN(R20 )2 wherein each R20 is the same or different H or alkyl group, preferably C1 to C4 alkyl, most preferably C1-C2 alkyl, and more preferably methyl;
(12) xe2x80x94CN; or
(13) alkyl; or
(2) R1 and X taken together form a group selected from: 
(3) X is selected from: xe2x95x90C(O), xe2x95x90C(NOR3), xe2x95x90C(NNR4R5), 
(4) M1 is carbon;
(5) M2 is selected from C or N;
(6) M3 and M4 are independently selected from C or N;
(7) Y is selected from: is xe2x80x94CH2xe2x80x94, xe2x95x90C(O), xe2x95x90C(NOR20) (wherein R20 is as defined above), or xe2x95x90C(S);
(8) Z is a C1-C6 alkyl group;
(9) R2 is a five or six-membered heteroaryl ring, said six-membered heteroaryl ring comprising 1 or 2 nitrogen atoms with the remaining ring atoms being carbon, and said five-membered heteroaryl ring containing 1 or 2 heteroatoms selected from: nitrogen, oxygen, or sulfur with the remaining ring atoms being carbon; said five or six membered heteroaryl rings being optionally substituted with 1 to 3 substituents independently selected from: halogen, hydroxyl, lower alkyl, lower alkoxy, xe2x80x94CF3, CF3Oxe2x80x94, xe2x80x94NR4R5, phenyl, xe2x80x94NO2, xe2x80x94CO2R4, xe2x80x94CON(R4)2 wherein each R4 is the same or different, xe2x80x94CH2NR4R5, xe2x80x94(N)C(NR4R5)2, or xe2x80x94CN;
(10) R3 is selected from:
(a) hydrogen;
(b) C1-C6 alkyl;
(c) aryl;
(d) heteroaryl;
(e) heterocycloalkyl;
(f) arylalkyl (e.g., aryl(C1 to C4)alkyl, e.g., xe2x80x94(CH2)waryl wherein w is 1 to 4, preferably 1 or 2, and most preferably 1, such as, for example xe2x80x94CH2phenyl or xe2x80x94CH2substituted phenyl);
(g) xe2x80x94(CH2)exe2x80x94C(O)N(R4)2 wherein each R4 is the same or different,
(h) xe2x80x94(CH2)exe2x80x94C(O)OR4;
(i) xe2x80x94(CH2)exe2x80x94C(O)R30 wherein R30 is a heterocycloalkyl group, such as, for example, morpholinyl, piperidinyl, piperazinyl or pyrrolidinyl, including 
(j) xe2x80x94CF3; or
(k) xe2x80x94CH2CF3;
wherein said aryl, heteroaryl, heterocycloalkyl, and the aryl portion of said arylalkyl are optionally substituted with 1 to 3 (preferably 1) substituents selected from: halogen (e.g., F or Cl), xe2x80x94OH, xe2x80x94OCF3, xe2x80x94CF3, xe2x80x94CN, xe2x80x94N(R45)2, xe2x80x94CO2R45, or xe2x80x94C(O)N (R45)2, wherein each R45 is independently selected from: H, alkyl, alkylaryl, or alkylaryl wherein said aryl moiety is substituted with 1 to 3 substituents independently selected from xe2x80x94CF3, xe2x80x94OH, halogen, alkyl, xe2x80x94NO2, or xe2x80x94CN;
(11) R4 is selected from: hydrogen, C1-C6 alkyl, aryl, alkylaryl, said aryl and alkylaryl groups being optionally substituted with 1 to 3 substituents selected from: halogen, xe2x80x94CF3, xe2x80x94OCF3, xe2x80x94OH, xe2x80x94N(R45)2, xe2x80x94CO2R45, xe2x80x94C(O)N(R45)2, or xe2x80x94CN; wherein R45 is as defined above;
(12) R5 is selected from: hydrogen, C1-C6 alkyl, xe2x80x94C(O)R4, xe2x80x94C(O)2R4, or xe2x80x94C(O)N(R4)2 wherein each R4 is independently selected, and R4 is as defined above;
(13) or R4 and R5 taken together with the nitrogen atom to which they are bound forms a five or six membered heterocycloalkyl ring (e.g., morpholine);
(14) R6 is selected from: alkyl, aryl, alkylaryl, halogen, hydroxyl, lower alkoxy, xe2x80x94CF3, CF3Oxe2x80x94, xe2x80x94NR4R5, phenyl, xe2x80x94NO2, xe2x80x94CO2R4, xe2x80x94CON(R4)2 wherein each R4 is the same or different, or xe2x80x94CN;
(15) R12 is selected from: alkyl, hydroxyl, alkoxy, or fluoro;
(16) R13 is selected from: alkyl, hydroxyl, alkoxy, or fluoro;
(17) a (subscript for R12) is 0 to 2;
(18) b (subscript for R13) is 0 to 2;
(19) c (subscript for R6) is 0 to 2;
(20) e is 0 to 5;
(21) m is 1 or 2;
(22) n is 1, 2 or 3; and
(23) p is 1, 2 or 3, with the proviso that when M3 and M4 are both nitrogen, then p is 2 or 3 (i.e., p is not 1 when M3 and M2 are both nitrogen).
This invention also provides a pharmaceutical composition comprising an effective amount of compound of Formula I, and a pharmaceutically acceptable carrier.
This invention further provides a method of treating: allergy, allergy-induced airway (e.g., upper airway) responses, congestion (e.g., nasal congestion), hypotension, cardiovascular disease, diseases of the GI tract, hyper and hypo motility and acidic secretion of the gastrointestinal tract, obesity, sleeping disorders (e.g., hypersomnia, somnolence, and narcolepsy), disturbances of the central nervous system, attention deficit hyperactivity disorder ADHD), hypo and hyperactivity of the central nervous system (for example, agitation and depression), and other CNS disorders (such as Alzheimer""s, schizophrenia, and migraine) comprising administering to a patient in need of such treatment (e.g., a mammal, such as a human being) an effective amount of a compound of Formula I.
This invention further provides a method of treating: allergy comprising administering to a patient in need of such treatment (e.g., a mammal, such as a human being) an effective amount of a compound of Formula I.
This invention further provides a method of treating: allergy-induced airway (e.g., upper airway) responses comprising administering to a patient in need of such treatment (e.g., a mammal, such as a human being) an effective amount of a compound of Formula I.
This invention further provides a method of treating: congestion (e.g., nasal congestion) comprising administering to a patient in need of such treatment (e.g., a mammal, such as a human being) an effective amount of a compound of Formula I.
This invention further provides a pharmaceutical composition comprising an effective amount of a compound of Formula I, and an effective amount of a H1 receptor antagonist in combination with a pharmaceutically acceptable carrier.
This invention further provides a method of treating: allergy, allergy-induced airway (e.g., upper airway) responses, and congestion (e.g., nasal congestion) comprising administering to a patient in need of such treatment (e.g., a mammal, such as a human being) an effective amount of a compound of Formula I in combination with an effective amount of an H1 receptor antagonist.
This invention further provides a method of treating: allergy comprising administering to a patient in need of such treatment (e.g., a mammal, such as a human being) an effective amount of a compound of Formula I in combination with an effective amount of an H1 receptor antagonist.
This invention further provides a method of treating: allergy-induced airway (e.g., upper airway) responses comprising administering to a patient in need of such treatment (e.g., a mammal, such as a human being) an effective amount of a compound of Formula I in combination with an effective amount of an H1 receptor antagonist.
This invention further provides a method of treating: congestion (e.g., nasal congestion) comprising administering to a patient in need of such treatment (e.g., a mammal, such as a human being) an effective amount of a compound of Formula I in combination with an effective amount of an H1 receptor antagonist.
As used herein, the following terms have the following meanings, unless indicated otherwise:
alkyl-(including the alkyl portions of alkoxy and alkylaryl)-represents straight and branched carbon chains and contains from one to twenty carbon atoms, preferably one to six carbon atoms;
alkylaryl-represents an alkyl group, as defined above, bound to an aryl group, as defined below, wherein said aryl group is bound to the rest of the molecule;
aryl (including the aryl portion of alkylaryl)-represents a carbocyclic group containing from 6 to 15 carbon atoms and having at least one aromatic ring (e.g., aryl is a phenyl ring), with all available substitutable carbon atoms of the carbocyclic group being intended as possible points of attachment;
arylalkyl-represents an aryl group, as defined above, bound to an alkyl group, as defined above, wherein said alkyl group is bound to the rest of the molecule;
cycloalkyl-represents saturated carbocyclic rings of from 3 to 20 carbon atoms, preferably 3 to 7 carbon atoms;
halo (halogen)-represents fluoro, chloro, bromo and iodo;
heteroaryl-represents cyclic groups, having at least one heteroatom selected from O, S or N, said heteroatom interrupting a carbocyclic ring structure and having a sufficient number of delocalized pi electrons to provide aromatic character, with the aromatic heterocyclic groups preferably containing from 2 to 14 carbon atoms; examples include but are not limited to isothiazolyl, isoxazolyl, furazanyl, triazolyl, thiazolyl, thienyl, furanyl (furyl), pyrrolyl, pyrazolyl, pyranyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyridyl (e.g., 2-, 3-, or 4-pyridyl), pyridyl N-oxide (e.g., 2-, 3-, or 4-pyridyl N-oxide), triazinyl, pteridinyl, indolyl (benzopyrrolyl), pyridopyrazinyl, isoqinolinyl, quinolinyl, quinoxolinyl, naphthyridinyl, wherein said pyridyl N-oxide can be represented as: 
heterocycloalkyl-represents a saturated, carbocylic ring containing from 3 to 15 carbon atoms, preferably from 4 to 6 carbon atoms, which carbocyclic ring is interrupted by 1 to 3 hetero groups selected from xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94 or xe2x80x94NR40xe2x80x94 wherein R40 represents C1 to C6 alkyl, arylalkyl, xe2x80x94C(O)R4, xe2x80x94C(O)OR4, or xe2x80x94C(O)N(R45)2 (wherein R45 is as defined above, and each R45 is independently selected); examples include but are not limited to 2- or 3-tetrahydrofuranyl, 2- or 3-tetrahydrothienyl, 2-, 3- or 4-piperidinyl, 2- or 3-pyrrolidinyl, 2- or 3-piperizinyl, 2- or 4-dioxanyl, 1,3-dioxolanyl, 1,3,5-trithianyl, pentamethylene sulfide, perhydroisoquinolinyl, decahydroquinolinyl, trimethylene oxide, azetidinyl, 1-azacycloheptanyl, 1,3-dithianyl, 1,3,5-trioxanyl, morpholinyl, thiomorpholinyl, 1,4-thioxanyl, and 1,3,5-hexahydrotriazinyl, thiazolidinyl, tetrahydropyranyl;
lower alkyl-represents an alkyl group, as defined above, that comprises 1 to 6 carbon atoms, preferably 1-4 carbon atoms;
lower alkoxy-represents an alkoxy group whose alkyl moiety comprises 1 to 6 carbon atoms, preferably 1-4 carbon atoms;
xe2x95x90C(O)-represents 
xe2x95x90C(NOR3)-represents 
wherein (1) represents a mixture of oxime isomers; (2) represents one geometric isomer of the oxime wherein the xe2x80x94OR3 group is on the same side of the double bond as the group to the left of the carbon atom; (3) represents one geometric isomer of the oxime wherein the xe2x80x94OR3 group is on the same side of the double bond as the group to the right of the carbon atom; and (1) can also be represented as: 
xe2x95x90C(NNR4R5) represents 
and represents a mixture of the isomers 
xe2x80x94(N)C(NR4R5)2 represents 
{circle around (N)} in the structure 
represents a nitrogen atom that is located at one of the 4 non-fused positions of the ring, i.e., positions 1, 2, 3 or 4 indicated below: 
AcOH-represents acetic acid;
t-BOC-represents t-butyloxycarbonyl;
Ci/mmol-represents curie/mmol (a measure of specific activity);
m-CPBA-represents m-chloroperbenzoic acid;
CSA-represents camphorsulfonic acid;
CBZ-represents carbonylbenzyloxy (xe2x80x94C(O)OCH2C6H5);
DBU-represents 1,8-diazabicyclo[5.4.0]undec-7-ene;
DBN-represents 1,5-diazabicyclo[4.3.0]non-5-ene;
DCC-represents dicyclohexylcarbodiimide;
Dibal-H-represents diisobutylaluminum hydride;
DIDPEA-represents N,N-diisopropylethylamine;
DMAP-represents 4-(dimethylamino)pyridine;
DEC-represents 2-diethylaminoethyl chloride hydrochloride;
DMF-represents dimethylformamide;
EDCI-represents 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide;
EtOAc-represents ethyl acetate;
EtOH-represents ethanol;
FMOC-represents 9-fluorenylmethoxycarbonyl;
HOBT-represents 1-hydroxybenzotriazole;
HPLC-represents high performance liquid chromatography;
HRMS-represents high resolution mass spectrometry;
Ki-represents inhibition constant for substrate/receptor complex;
LAH-lithium aluminum hydride;
LDA-represents lithium diisopropylamide;
LRMS-represents low resolution mass spectrometry;
MeOH-represents methanol;
NaBH(OAc)3-represents sodium triacetoxyborohydride;
NaBH4-represents sodium borohydride;
NaBH3CN-represents sodium cyanoborohydride;
NaHMDS-represents sodium hexamethyl disilylazide;
nM-represents nanomolar;
pA2-represents-log EC50, as defined by J. Hey, Eur. J. Pharmacol., (1995), Vol. 294, 329-335;
PCC-represents pyridinium chlorochromate;
PyBOP-represents benzotriazole-1-yl-oxy-trispyrrolidino-phosphonium hexaflurophosphate;
TEMPO-represents 2,2,6,6-tetramethyl-1-piperidinyloxy, free radical;
TFA-represents trifluoroacetic acid;
TMAD-represents N,N,Nxe2x80x2,Nxe2x80x2-tetramethylazodicarboxamide;
TMEDA-represents tetramethylethylenediamine;
Tr-represents triphenylmethyl;
Tris-represents tris(hydroxymethyl)aminomethane;and
p-TsOH-represents p-toluenesulfonic acid.
Also, as used herein, xe2x80x9cupper airwayxe2x80x9d usually means the upper respiratory systemxe2x80x94i.e., the nose, throat, and associated structures.
Also, as used herein, xe2x80x9ceffective amountxe2x80x9d generally means a therapeutically effective amount.
Lines drawn into the rings indicate that the indicated bond may be attached to any of the substitutable ring carbon atoms.
Certain compounds of the invention may exist in different isomeric (e.g., enantiomers, diastereoisomers and geometric) forms. The invention contemplates all such isomers both in pure form and in admixture, including racemic mixtures. Enol forms are also included.
The compounds of this invention are ligands for the histamine H3 receptor. The compounds of this invention can also be described as antagonists of the H3 receptor, or as H3 antagonists.
The compounds of the invention are basic and form pharmaceutically acceptable salts with organic and inorganic acids. Examples of suitable acids for such salt formation are hydrochloric, sulfuric, phosphoric, acetic, citric, oxalic, malonic, salicylic, malic, fumaric, succinic, ascorbic, maleic, methanesulfonic and other mineral and carboxylic acids well known to those skilled in the art. The salts are prepared by contacting the free base form with a sufficient amount of the desired acid to produce a salt in the conventional manner. The free base forms may be regenerated by treating the salt with a suitable dilute aqueous base solution such as dilute aqueous sodium hydroxide, potassium carbonate, ammonia and sodium bicarbonate. The free base forms differ from their corresponding salt forms somewhat in certain physical properties, such as solubility in polar solvents, but the salts are otherwise equivalent to their corresponding free base forms for purposes of this invention.
The compounds of Formula I can exist in unsolvated as well as solvated forms, including hydrated forms, e.g., hemi-hydrate. In general, the solvated forms, with pharmaceutically acceptable solvents such as water, ethanol and the like are equivalent to the unsolvated forms for purposes of the invention.
The compounds of this invention can be combined with an H1 receptor antagonist (i.e., the compounds of this invention can be combined with an H1 receptor antagonist in a pharmaceutical composition, or the compounds of this invention can be administered with H1 receptor antagonist).
Numerous chemical substances are known to have histamine H1 receptor antagonist activity. Many useful compounds can be classified as ethanolamines, ethylenediamines, alkylamines, phenothiazines or piperidines. Representative H1 receptor antagonists include, without limitation: astemizole, azatadine, azelastine, acrivastine, brompheniramine, cetirizine, chlorpheniramine, clemastine, cyclizine, carebastine, cyproheptadine, carbinoxamine, descarboethoxyloratadine (also known as SCH-34117), diphenhydramine, doxylamine, dimethindene, ebastine, epinastine, efletirizine, fexofenadine, hydroxyzine, ketotifen, loratadine, levocabastine, meclizine, mizolastine, mequitazine, mianserin, noberastine, norastemizole, picumast, pyrilamine, promethazine, terfenadine, tripelennamine, temelastine, trimeprazine and triprolidine. Other compounds can readily be evaluated to determine activity at H1 receptors by known methods, including specific blockade of the contractile response to histamine of isolated guinea pig ileum. See for example, WO98/06394 published Feb. 19, 1998.
Thus, in the methods of this invention wherein a compound of Formula I is combined with an effective amount of an H1 receptor antagonist, said H1 receptor antagonist is selected from: astemizole, azatadine, azelastine, acrivastine, brompheniramine, cetirizine, chlorpheniramine, clemastine, cyclizine, carebastine, cyproheptadine, carbinoxamine, descarboethoxyloratadine, diphenhydramine, doxylamine, dimethindene, ebastine, epinastine, efletirizine, fexofenadine, hydroxyzine, ketotifen, loratadine, levocabastine, meclizine, mizolastine, mequitazine, mianserin, noberastine, norastemizole, picumast, pyrilamine, promethazine, terfenadine, tripelennamine, temelastine, trimeprazine or triprolidine.
Also, in the methods of this invention wherein a compound of Formula I is combined with an effective amount of an H1 receptor antagonist, said H1 receptor antagonist is selected from: astemizole, azatadine, azelastine, brompheniramine, cetirizine, chlorpheniramine, clemastine, carebastine, descarboethoxyloratadine, diphenhydramine, doxylamine, ebastine, fexofenadine, loratadine, levocabastine, mizolastine, norastemizole, or terfenadine.
Also, in the methods of this invention wherein a compound of Formula I is combined with an effective amount of an H1 receptor antagonist, said H1 receptor antagonist is selected from: azatadine, brompheniramine, cetirizine, chlorpheniramine, carebastine, descarboethoxyloratadine (also known as SCH-34117), diphenhydramine, ebastine, fexofenadine, loratadine, or norastemizole.
Also, in the methods of this invention wherein a compound of Formula I is combined with an effective amount of an H1 receptor antagonist, said H1 receptor antagonist is loratadine.
Also, in the methods of this invention wherein a compound of Formula I is combined with an effective amount of an H1 receptor antagonist, said H1 receptor antagonist is descarboethoxyloratadine.
Also, in the methods of this invention wherein a compound of Formula I is combined with an effective amount of an H1 receptor antagonist, said H1 receptor antagonist is fexofenadine.
Also, in the methods of this invention wherein a compound of Formula I is combined with an effective amount of an H1 receptor antagonist, said H1 receptor antagonist is cetirizine.
Preferably, in the above methods, allergy-induced airway responses are treated.
Also, preferably, in the above methods, allergy is treated.
Also, preferably, in the above methods, nasal congestion is treated.
Preferably, in the above methods using a combination of a compound of Formula I (H3 antagonist) and an H1 antagonist, the H1 antagonist is selected from: loratadine, descarboethoxyloratadine, fexofenadine or cetirizine. Most preferably the H1 antagonist is loratadine or descarboethoxyloratadine.
In the methods of this invention wherein a combination of an H3 antagonist of this invention (compound of Formula I) is administered with a H1 antagonist, the antagonists can be administered simultaneously, consecutively (one after the other within a relatively short period of time), or sequentially (first one and then the other over a period of time). In general, when the antagonists are administered consecutively or sequentially, the H3 antagonist of this invention (compound of Formula I) is administered first.
Thus, one emodiment of this invention is directed to a pharmaceutical composition comprising an effective amount of Compound 32 and a pharmaceutically acceptable carrier.
Another emodiment of this invention is directed to a pharmaceutical composition comprising an effective amount of Compound 54 and a pharmaceutically acceptable carrier.
Another emodiment of this invention is directed to a pharmaceutical composition comprising an effective amount of Compound 55 and a pharmaceutically acceptable carrier.
Another emodiment of this invention is directed to a pharmaceutical composition comprising an effective amount of Compound 253A and a pharmaceutically acceptable carrier.
Another emodiment of this invention is directed to a pharmaceutical composition comprising an effective amount of Compound 287 and a pharmaceutically acceptable carrier.
Another emodiment of this invention is directed to a pharmaceutical composition comprising an effective amount of Compound 320 and a pharmaceutically acceptable carrier.
Another embodiment of this invention is directed to a method of treating: allergy, allergy-induced airway responses, congestion, hypotension, cardiovascular disease, hypotension, diseases of the GI tract, hyper and hypo motility and acidic secretion of the gastrointestinal tract, obesity, sleeping disorders, disturbances of the central nervous system, attention deficit hyperactivity disorder, hypo and hyperactivity of the central nervous system, Alzheimer""s disease, schizophrenia, and migraine comprising administering to a patient in need of such treatment an effective amount of Compound 32.
Another embodiment of this invention is directed to a method of treating: allergy, allergy-induced airway responses, congestion, hypotension, cardiovascular disease, hypotension, diseases of the GI tract, hyper and hypo motility and acidic secretion of the gastrointestinal tract, obesity, sleeping disorders, disturbances of the central nervous system, attention deficit hyperactivity disorder, hypo and hyperactivity of the central nervous system, Alzheimer""s disease, schizophrenia, and migraine comprising administering to a patient in need of such treatment an effective amount of Compound 54.
Another embodiment of this invention is directed to a method of treating: allergy, allergy-induced airway responses, congestion, hypotension, cardiovascular disease, hypotension, diseases of the GI tract, hyper and hypo motility and acidic secretion of the gastrointestinal tract, obesity, sleeping disorders, disturbances of the central nervous system, attention deficit hyperactivity disorder, hypo and hyperactivity of the central nervous system, Alzheimer""s disease, schizophrenia, and migraine comprising administering to a patient in need of such treatment an effective amount of Compound 55.
Another embodiment of this invention is directed to a method of treating: allergy, allergy-induced airway responses, congestion, hypotension, cardiovascular disease, hypotension, diseases of the GI tract, hyper and hypo motility and acidic as secretion of the gastro-intestinal tract, obesity, sleeping disorders, disturbances of the central nervous system, attention deficit hyperactivity disorder, hypo and hyperactivity of the central nervous system, Alzheimer""s disease, schizophrenia, and migraine comprising administering to a patient in need of such treatment an effective amount of Compound 253A.
Another embodiment of this invention is directed to a method of treating: allergy, allergy-induced airway responses, congestion, hypotension, cardiovascular disease, hypotension, diseases of the GI tract, hyper and hypo motility and acidic secretion of the gastro-intestinal tract, obesity, sleeping disorders, disturbances of the central nervous system, attention deficit hyperactivity disorder, hypo and hyperactivity of the central nervous system, Alzheimer""s disease, schizophrenia, and migraine comprising administering to a patient in need of such treatment an effective amount of Compound 287.
Another embodiment of this invention is directed to a method of treating: allergy, allergy-induced airway responses, congestion, hypotension, cardiovascular disease, hypotension, diseases of the GI tract, hyper and hypo motility and acidic secretion of the gastro-intestinal tract, obesity, sleeping disorders, disturbances of the central nervous system, attention deficit hyperactivity disorder, hypo and hyperactivity of the central nervous system, Alzheimer""s disease, schizophrenia, and migraine comprising administering to a patient in need of such treatment an effective amount of Compound 320.
Another embodiment of this invention is directed to a method of treating allergy-induced airway responses comprising administering to a patient in need of such treatment an effective amount of Compound 32.
Another embodiment of this invention is directed to a method of treating allergy-induced airway responses comprising administering to a patient in need of such treatment an effective amount of Compound 54.
Another embodiment of this invention is directed to a method of treating allergy-induced airway responses comprising administering to a patient in need of such treatment an effective amount of Compound 55.
Another embodiment of this invention is directed to a method of treating allergy-induced airway responses comprising administering to a patient in need of such treatment an effective amount of Compound 253A.
Another embodiment of this invention is directed to a method of treating allergy-induced airway responses comprising administering to a patient in need of such treatment an effective amount of Compound 287.
Another embodiment of this invention is directed to a method of treating allergy-induced airway responses comprising administering to a patient in need of such treatment an effective amount of Compound 320.
Another embodiment of this invention is directed to a method of treating allergy or nasal congestion comprising administering to a patient in need of such treatment an effective amount of Compound 32.
Another embodiment of this invention is directed to a method of treating allergy or nasal congestion comprising administering to a patient in need of such treatment an effective amount of Compound 54.
Another embodiment of this invention is directed to a method of treating allergy or nasal congestion comprising administering to a patient in need of such treatment an effective amount of Compound 55.
Another embodiment of this invention is directed to a method of treating allergy or nasal congestion comprising administering to a patient in need of such treatment an effective amount of Compound 253A.
Another embodiment of this invention is directed to a method of treating allergy or nasal congestion comprising administering to a patient in need of such treatment an effective amount of Compound 287.
Another embodiment of this invention is directed to a method of treating allergy or nasal congestion comprising administering to a patient in need of such treatment an effective amount of Compound 320.
Another embodiment of this invention is directed to a pharmaceutical composition comprising an effective amount of Compound 32, and an effective amount of H1 receptor antagonist, and a pharmaceutically effective carrier.
Another embodiment of this invention is directed to a pharmaceutical composition comprising an effective amount of Compound 54, and an effective amount of H1 receptor antagonist, and a pharmaceutically effective carrier.Another embodiment of this invention is directed to a pharmaceutical composition comprising an effective amount of Compound 55, and an effective amount of H1 receptor antagonist, and a pharmaceutically effective carrier.
Another embodiment of this invention is directed to a pharmaceutical composition comprising an effective amount of Compound 253A, and an effective amount of H1 receptor antagonist, and a pharmaceutically effective carrier.
Another embodiment of this invention is directed to a pharmaceutical composition comprising an effective amount of Compound 287, and an effective amount of H1 receptor antagonist, and a pharmaceutically effective carrier.Another embodiment of this invention is directed to a pharmaceutical composition comprising an effective amount of Compound 320, and an effective amount of H1 receptor antagonist, and a pharmaceutically effective carrier.
Another embodiment of this invention is directed to a method of treating: allergy, allergy-induced airway responses, and congestion comprising administering to a patient in need of such treatment an effective amount of Compound 32 in combination with an effective amount of an H1 receptor antagonist.
Another embodiment of this invention is directed to a method of treating: allergy, allergy-induced airway responses, and congestion comprising administering to a patient in need of such treatment an effective amount of Compound 54 in combination with an effective amount of an H1 receptor antagonist.
Another embodiment of this invention is directed to a method of treating: allergy, allergy-induced airway responses, and congestion comprising administering to a patient in need of such treatment an effective amount of a Compound 55 in combination with an effective amount of an H1 receptor antagonist.Another embodiment of this invention is directed to a method of treating: allergy, allergy-induced airway responses, and congestion comprising administering to a patient in need of such treatment an effective amount of Compound 253A in combination with an effective amount of an H1 receptor antagonist.
Another embodiment of this invention is directed to a method of treating: allergy, allergy-induced airway responses, and congestion comprising administering to a patient in need of such treatment an effective amount of Compound 287 in combination with an effective amount of an H1 receptor antagonist.
Another embodiment of this invention is directed to a method of treating: allergy, allergy-induced airway responses, and congestion comprising administering to a patient in need of such treatment an effective amount of Compound 320 in combination with an effective amount of an H1 receptor antagonist.
Another embodiment of this invention is directed to a method of treating: allergy, allergy-induced airway responses, and congestion comprising administering to a patient in need of such treatment an effective amount of Compound 32 in combination with an effective amount of an H1 receptor antagonist selected from: astemizole, azatadine, azelastine, acrivastine, brompheniramine, cetirizine, chlorpheniramine, clemastine, cyclizine, carebastine, cyproheptadine, carbinoxamine, descarboethoxyloratadine, diphenhydramine, doxylamine, dimethindene, ebastine, epinastine, efletirizine, fexofenadine, hydroxyzine, ketotifen, loratadine, levocabastine, meclizine, mizolastine, mequitazine, mianserin, noberastine, norastemizole, picumast, pyrilamine, promethazine, terfenadine, tripelennamine, temelastine, trimeprazine or triprolidine.
Another embodiment of this invention is directed to a method of treating: allergy, allergy-induced airway responses, and congestion comprising administering to a patient in need of such treatment an effective amount of Compound 54 in combination with an effective amount of an H1 receptor antagonist selected from: astemizole, azatadine, azelastine, acrivastine, brompheniramine, cetirizine, chlorpheniramine, clemastine, cyclizine, carebastine, cyproheptadine, carbinoxamine, descarboethoxyloratadine, diphenhydramine, doxylamine, dimethindene, ebastine, epinastine, efletirizine, fexofenadine, hydroxyzine, ketotifen, loratadine, levocabastine, meclizine, mizolastine, mequitazine, mianserin, noberastine, norastemizole, picumast, pyrilamine, promethazine, terfenadine, tripelennamine, temelastine, trimeprazine or triprolidine.
Another embodiment of this invention is directed to a method of treating: allergy, allergy-induced airway responses, and congestion comprising administering to a patient in need of such treatment an effective amount of Compound 55 in combination with an effective amount of an H1 receptor antagonist selected from: astemizole, azatadine, azelastine, acrivastine, brompheniramine, cetirizine, chlorpheniramine, clemastine, cyclizine, carebastine, cyproheptadine, carbinoxamine, descarboethoxyloratadine, diphenhydramine, doxylamine, dimethindene, ebastine, epinastine, efletirizine, fexofenadine, hydroxyzine, ketotifen, loratadine, levocabastine, meclizine, mizolastine, mequitazine, mianserin, noberastine, norastemizole, picumast, pyrilamine, promethazine, terfenadine, tripelennamine, temelastine, trimeprazine or triprolidine.
Another embodiment of this invention is directed to a method of treating: allergy, allergy-induced airway responses, and congestion comprising administering to a patient in need of such treatment an effective amount of Compound 253A in combination with an effective amount of an H1 receptor antagonist selected from: astemizole, azatadine, azelastine, acrivastine, brompheniramine, cetirizine, chlorpheniramine, clemastine, cyclizine, carebastine, cyproheptadine, carbinoxamine, descarboethoxyloratadine, diphenhydramine, doxylamine, dimethindene, ebastine, epinastine, efletirizine, fexofenadine, hydroxyzine, ketotifen, loratadine, levocabastine, meclizine, mizolastine, mequitazine, mianserin, noberastine, norastemizole, picumast, pyrilamine, promethazine, terfenadine, tripelennamine, temelastine, trimeprazine or triprolidine.
Another embodiment of this invention is directed to a method of treating: allergy, allergy-induced airway responses, and congestion comprising administering to a patient in need of such treatment an effective amount of Compound 287 in combination with an effective amount of an H1 receptor antagonist selected from: astemizole, azatadine, azelastine, acrivastine, brompheniramine, cetirizine, chlorpheniramine, clemastine, cyclizine, carebastine, cyproheptadine, carbinoxamine, descarboethoxyloratadine, diphenhydramine, doxylamine, dimethindene, ebastine, epinastine, efletirizine, fexofenadine, hydroxyzine, ketotifen, loratadine, levocabastine, meclizine, mizolastine, mequitazine, mianserin, noberastine, norastemizole, picumast, pyrilamine, promethazine, terfenadine, tripelennamine, temelastine, trimeprazine or triprolidine.
Another embodiment of this invention is directed to a method of treating: allergy, allergy-induced airway responses, and congestion comprising administering to a patient in need of such treatment an effective amount of Compound 320 in combination with an effective amount of an H1 receptor antagonist selected from: astemizole, azatadine, azelastine, acrivastine, brompheniramine, cetirizine, chlorpheniramine, clemastine, cyclizine, carebastine, cyproheptadine, carbinoxamine, descarboethoxyloratadine, diphenhydramine, doxylamine, dimethindene, ebastine, epinastine, efletirizine, fexofenadine, hydroxyzine, ketotifen, loratadine, levocabastine, meclizine, mizolastine, mequitazine, mianserin, noberastine, norastemizole, picumast, pyrilamine, promethazine, terfenadine, tripelennamine, temelastine, trimeprazine or triprolidine.
Another embodiment of this invention is directed to a method of treating: allergy, allergy-induced airway responses, and congestion comprising administering to a patient in need of such treatment an effective amount of Compound 32 in combination with an effective amount of an H1 receptor antagonist selected from: loratadine, descarboethoxyloratadine, fexofenadine or cetirizine.
Another embodiment of this invention is directed to a method of treating: allergy, allergy-induced airway responses, and congestion comprising administering to a patient in need of such treatment an effective amount of Compound 54 in combination with an effective amount of an H1 receptor antagonist selected from: loratadine, descarboethoxyloratadine, fexofenadine or cetirizine.
Another embodiment of this invention is directed to a method of treating: allergy, allergy-induced airway responses, and congestion comprising administering to a patient in need of such treatment an effective amount of Compound 55 in combination with an effective amount of an H1 receptor antagonist selected from: loratadine, descarboethoxyloratadine, fexofenadine or cetirizine.
Another embodiment of this invention is directed to a method of treating: allergy, allergy-induced airway responses, and congestion comprising administering to a patient in need of such treatment an effective amount of Compound 253A in combination with an effective amount of an H1 receptor antagonist selected from: loratadine, descarboethoxyloratadine, fexofenadine or cetirizine.
Another embodiment of this invention is directed to a method of treating: allergy, allergy-induced airway responses, and congestion comprising administering to a patient in need of such treatment an effective amount of Compound 287 in combination with an effective amount of an H1 receptor antagonist selected from: loratadine, descarboethoxyloratadine, fexofenadine or cetirizine.
Another embodiment of this invention is directed to a method of treating: allergy, allergy-induced airway responses, and congestion comprising administering to a patient in need of such treatment an effective amount of Compound 320 in combination with an effective amount of an H1 receptor antagonist selected from: loratadine, descarboethoxyloratadine, fexofenadine or cetirizine.
Another embodiment of this invention is directed to a method of treating: allergy, allergy-induced airway responses, and congestion comprising administering to a patient in need of such treatment an effective amount of Compound 32 in combination with an effective amount of an H1 receptor antagonist selected from: loratadine or descarboethoxyloratadine.
Another embodiment of this invention is directed to a method of treating: allergy, allergy-induced airway responses, and congestion comprising administering to a patient in need of such treatment an effective amount of Compound 54 in combination with an effective amount of an H1 receptor antagonist selected from: loratadine or descarboethoxyloratadine.
Another embodiment of this invention is directed to a method of treating: allergy, allergy-induced airway responses, and congestion comprising administering to a patient in need of such treatment an effective amount of Compound 55 in combination with an effective amount of an H1 receptor antagonist selected from: loratadine or descarboethoxyloratadine.
Another embodiment of this invention is directed to a method of treating: allergy, allergy-induced airway responses, and congestion comprising administering to a patient in need of such treatment an effective amount of Compound 253A in combination with an effective amount of an H1 receptor antagonist selected from: loratadine or descarboethoxyloratadine.
Another embodiment of this invention is directed to a method of treating: allergy, allergy-induced airway responses, and congestion comprising administering to a patient in need of such treatment an effective amount of Compound 287 in combination with an effective amount of an H1 receptor antagonist selected from: loratadine or descarboethoxyloratadine.
Another embodiment of this invention is directed to a method of treating: allergy, allergy-induced airway responses, and congestion comprising administering to a patient in need of such treatment an effective amount of Compound 320 in combination with an effective amount of an H1 receptor antagonist selected from: loratadine or descarboethoxyloratadine.
R1 is preferably selected from:
(A) aryl (most preferably phenyl);
(B) substituted aryl (e.g., substituted phenyl), wherein the substituents on said substitued aryl are most preferably selected from: (1) halo (e.g., monohalo or dihalo), more preferably chloro or fluoro, even more preferably monochloro, dichloro, monofluoro or difluoro; or (2) alkyl, more preferably unbranched (i.e., straight chain, e.g., methyl) alkyl, even more preferably substituted alkyl, still more preferably alkyl substituted with halo (e.g., 1, 2 or 3 halo atoms, such as Cl or F), even still more preferably alkyl substituted with fluoro atoms, yet still more preferably trifluromethyl;
(C) heteroaryl, most preferably a five or six membered heteroaryl ring, more preferably a six membered heteroaryl ring, and still more preferably pyridyl, examples of heteroaryl rings include pyridyl, thienyl, pyrimidinyl, thiazolyl or pyridyl N-Oxide, most preferred heteroaryl rings are exemplified by 
is preferred more;
(D) substituted heteroaryl, most preferably halo or alkyl substituted heteroaryl (e.g., halopyridyl (e.g., fluoropyridyl) and alkylthiazolyl), more preferably substituted heteroaryl wherein the substituents are independently selected from the same or different alkyl groups (even more preferably one straight chain alkyl group, e.g., methyl), still more preferably alkyl substituted thiazolyl, and even more preferably 
yet even more preferably 
(E) when R1 is taken together with X, then the moiety is 
wherein c is most preferably 0 or 1, and when c is 1 then R6 is most preferably halo, and when c is 1 then R6 is more preferably fluoro.
X is preferably xe2x95x90C(NOR3) wherein R3 is preferably selected from H, alkyl or halo substituted alkyl (e.g., fluoro substituted alkyl, such as xe2x80x94CH2CF3), most preferably alkyl, more preferably methyl or ethyl, and still more preferably methyl.
Preferably M2 is nitrogen.
n is preferably 2.
a is preferably 0 or 1, and most preferably 0.
b is preferably 0 or 1, and most preferably 0.
c is preferably 0 or 1, and most preferably 0, and when c is 1 then R6 is preferably halo, and when c is 1 R6 is most preferably fluoro.
e is preferably 1-5.
Y is preferably xe2x95x90C(O) (i.e., xe2x95x90Cxe2x95x90O).
M3 and M4 are preferably selected such that: (1) one is carbon and the other is nitrogen, or (2) both are nitrogen, with M3 most preferably being carbon.
p is preferably 2.
Z is preferably C1 to C3 alkyl, and most preferably
xe2x80x94CH2xe2x80x94 or 
R2 is preferably a six membered heteroaryl ring, most preferably pyridyl, substituted pyridyl, pyrimidinyl or substituted pyrimidinyl, more preferably pyridyl, pyridyl substituted with xe2x80x94NR4R5, pyrimidinyl or pyrimidinyl substituted with xe2x80x94NR4R5, still more preferably pyridyl, pyridyl substituted with xe2x80x94NH2 (i.e., R4 and R5 are H), pyrimidinyl or pyrimidinyl substituted with xe2x80x94NH2 (i.e., R4 and R5 are H), and even more preferably 
and still even more preferably 
R3 is preferably H or alkyl, most preferably H or methyl.
R4 is preferably H or lower alkyl, most preferably H or methyl, and more preferably H.
R5 is preferably H, C1 to C6alkyl or xe2x80x94C(O)R4, most preferably H or methyl, and more preferably H.
R12 is preferably alkyl, hydroxyl or fluoro, and most preferably H.
R13 is preferably alkyl, hydroxyl or fluoro, and most preferably H.
Representative compounds of this invention include, but are not limited to: Compounds 23, 30, 31, 32, 33, 41, 44, 45, 49, 50, 52, 53, 54, 55, 56, 57A, 59, 65, 75, 76, 80, 82, 83, 88, 92, 99, 104, 105, 110, 111, 117, 121, 123, 127, 128, 200-241, 244-273, 275, and 278-282, 287, 296, 301-439 and 446.
Thus, representative compounds of this invention include, but are not limited to: Compounds 23, 30, 31, 32, 33, 44, 45, 49, 50, 53, 54, 55, 59, 75, 76, 83, 88, 92, 99, 104, 110, 117, 128, 200, 201, 203-215, 217-241, 244-246, 246A, 247-253, 253A, 254-273, 275, 278, and 280-282, 317, 334 and 403.
Preferred compounds of this invention are selected from: Compound 23, 30, 31, 32, 33, 50, 53, 54, 55, 56, 57A, 59, 92, 212, 215, 218, 219, 220, 224, 225, 226, 227, 229, 233, 235, 237, 238, 246, 246A, 247, 248, 251, 253, 253A, 268-273, 275, 278-281, 287, 296, 301, 304-307, 309, 312, 314-318, 320-356, or 358-376.
Most preferred compounds of this invention are selected from: Compound 30, 31, 32, 33, 54, 55, 56, 57A, 225, 237, 246A, 253A, 273, 280, 287, 296, 301, 304-307, 309, 312, 314-318, 320-348, 350-356, 359-372, and 374-376.
Thus, one embodiment of this invention is directed to Compound 32.
Another embodiment of this invention is directed to Compound 54.
Another embodiment of this invention is directed to Compound 55.
Another embodiment of this invention is directed to Compound 253A.
Another embodiment of this invention is directed to Compound 287.
Another embodiment of this invention is directed to Compound 320.
Structures for the above compounds are found in the Examples below, and in Tables 1 to 3 below.
The more preferred compound of this invention is the compound of the formula: 
This invention also provides a compound of the formula: 
This invention also provides a compound of the formula: 
Compounds 32A and 32B can also be used in the pharmaceutical compositions, and the methods of this invention.
The following processes may be employed to produce compounds of the invention.
One synthetic route involves a linear sequence of reactions to obtain the desired compounds, i.e.,
A+Bxe2x86x92AB+Cxe2x86x92ABC+Dxe2x86x92ABCD
This linear sequence of reactions to synthesize compounds of this invention is illustrated below. In the illustrated procedure R1 is aryl, heteroaryl, or alkyl; X=a ketone, oxime or substituted oxime; M1=M3=carbon; M2=M4=nitrogen; Y is Cxe2x95x90O; Zxe2x95x90CHR; R2 is heteroaryl; and n and m=2 (n and m being 1 can also be prepared by this procedure). 
In the above equations PG represents a protecting group, and M represents Li or MgX1 (wherein X1 represents Cl, Br or I).
In equation 1 and 2, a Grignard reagent 2 is reacted with an electrophile such as the aldehyde 1 or the nitrile 4 in a suitable aprotic solvent such as THF or ether. PG represents a protecting group. Suitable protecting groups include, for example, methyl and benzyl. In the case of nitrile 4, acidic workup yields the ketone 8 directly. Alcohol 3 can be oxidized by a number of different reagents to give 8. Alternatively, the amide 7 can be reacted with an organometallic reagent to directly give the ketone 8. Suitable protecting groups for this step include carbamates or amides or the like. Thus, examples of protecting groups in equation 3 include t-BOC, CBZ and FMOC. 
When the protecting group, PG, is a methyl group, said methyl group can be removed using a reagent such as a chloroformate; when PG is a carbamate, such as, a t-Boc group, it can be removed by dilute acid, such as, for example HCl. 
Amine 9 can be coupled to acid 10 using a number of methods well known in the art such as DCC or PyBOP. Alternatively, the acid 10 can be activated by conversion to the acid chloride or mixed anhydride and then reacted with the amine 9 to give 11. Suitable protecting groups for 10 include, for example, t-Boc. 
Compound 11 in which the protecting group is a t-Boc can be deprotected under acidic conditions such as HCl in dioxane or TFA in CH2Cl2 to give the amine 12. 
R30 in 13 represents an alkyl group. E is a leaving group, halogen, or E is a carbonyl group.
Compound 14 can be prepared by reacting amine 12 with 13. When E represents a carbonyl group (Cxe2x95x90O), 12 and 13 are combined in a solvent such as CH2Cl2 in the presence of molecular sieves. After the reaction is complete (e.g.,1 to 10 h), a reducing agent such as NaBH(OAc)3 is added. Alternatively, when E is a halogen atom such as Cl or Br, 12 and 13 are combined in a solvent, such as DMF, in the presence of a tertiary amine base to give the product 14. Suitable protecting groups include, for example t-Boc, phthaloyl. 
Compound 14 can be converted to the oxime 15 by combining 14 with H2NOR3.HCl in pyridine at a temperature of 40-60xc2x0 C. Alternatively, 14 can be combined with H2NOR3.HCl in an alcoholic solvent in the presence of a base, such as, NaOAc, to give 15.
An alternate approach to the synthesis of compounds of Formula I involves the synthesis of the two halves of the molecule followed by coupling of the two pieces, i.e.,
A+Bxe2x86x92AB
C+Dxe2x86x92CD
AB+CDxe2x86x92ABCD
In this case, the synthesis of the AB fragment is the same as that described above. The synthesis of the CD fragment is given below. 
R30 is as defined above (i.e., alkyl). R35 is methyl or ethyl.
Compound 17 is synthesized in the same manner as that described for the synthesis of compound 14. 
M represents Li, Na, or K.
Compound 17 is saponified in a mixed solvent, such as, for example: (1) EtOH or MeOH and water, or (2) THF, water, and MeOH, using an alkali metal base such as LiOH or NaOH at a temperature of from 50 to 100xc2x0 C. to give the salt 18.
Compound 18 can be combined with compound 9, as described above, to give 14. The remaining steps are the same.
Compounds useful in this invention are exemplified by the following examples which should not be construed as limiting the scope of the disclosure. Alternative mechanistic pathways and analogous structures within the scope of the invention may be apparent to those skilled in the art.